DETAILED ACTION
Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant's election with traverse of the invention of Group I (amended claim listing filed on 07/14/2025 with Group I, claims 1, 5, 7-9, and 13-16) in the reply filed on 07/14/2025 is acknowledged.
The traversal is on the ground(s) that the restriction of the claims on the grounds that searching each of the groups would not prove unduly burdensome.
This is not found persuasive because the elected Group I is directed to a process (a method) and the restricted Groups II and Group III are directed to an apparatus. The claimed process (a method) is classified in G01N33/56983, G01N2470/04, G01N2333/165, and G01N2469/20 and the claimed Group II apparatus is classified in G01N33/54366, G01N 33/5302, G16H 10/00, A61B 1/0002; whereas the claimed Group II apparatus is classified in B01D 2313/701, G06N 1/00, A61B 6/5205, A61H 2201/5007, A61B 2034/2074. The inventions of Groups I, II and III as recited supra have acquired a different classification status. A separate classification is prima facie evidence of search burden. See MPEP § 808.02.
Therefore, the Election/Restriction is appropriate as indicated in office action dated 05/15/2025.
The requirement is still deemed proper and is therefore made FINAL.
Priority
3. This application claims priority to U.S. Provisional Patent Application No. 63/212,862, filed June 21, 2021.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on 08/26/2022, 11/28/2022, 01/22/2025, and 10/09/2025 is in compliance with the provisions of 37 CFR 1.97 and, the information disclosure statement is being considered by the examiner.
Status of Claims
5. Claims 1, 5, 9 and 14-19 as filed on 11/21/2025 are pending.
6. Applicant cancelled claims 7-8 and 13 as per amendment filing dated 11/21/2025.
7. Claims 17-19 are withdrawn from consideration due to office action Election/Restriction 05/15/2025.
8. The inventions of elected Group I, claims 1, 5, 9 and 14-19 are under examination in this office action.
Claim Interpretation (Modified)
9. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claims 1, 5, and 9 are interpreted as directed to a method for measuring and reporting antibodies to SARS CoV-2 in dried blood spot (DBS) or dried plasma spot sample of a subject calculated as a numerical value, a defined cutoff index (COI) numerical value indicative of positive (COI >2.0), negative (COI <0.65) and an indeterminate (> 0.65 COI and < 2.0 COI) sample type , and further modification of the method to perform assay with the dried plasma sample. The claim 1 incorporate a limitation on dilution of the sample that occurs during extraction of the SARS-CoV-2 specific analyte from the dried sample (DBS or dried plasma sample) and the measured value is divided by a fractional cutoff to account for the dilution so as to provide a normalized COI value. The claims do not recite a specific assay type (e.g ELISA) therefore any assay type that can detect and quantify the antibodies to SARS CoV-2 antigen(s) can be practiced. The claim 9 is directed to incorporate dilution of the sample that occurs during extraction of the SARS-CoV-2 specific analyte from the dried sample (DBS or dried plasma sample) and the measured value is divided by a fractional cutoff to account for the dilution so as to provide a normalized COI value, the normalized COI comprises a cutoff value for serum.
Claims 14-16 (dependent on claim 1) are interpreted as directed to a modified method of claim 1 to detect and quantify the antibodies to SARS CoV-2 antigen(s) in DBS based on the principle of electrochemical luminescent emission assay inter alia comprising a first antigen labeled with a detectable electrochemical moiety and a second antigen labeled with a binding agent streptavidin. The eluted antibody from the DBS binds to the first and second antigen forming a sandwich and the sandwich complex binds to a biotin-labeled electrode via streptavidin label on the second antigen and application of a voltage results in chemiluminescent emission. The calculated COI values are indicative of positive (COI >2.0), negative (COI <0.65) and an indeterminate (> 0.65 COI and < 2.0 COI) sample type.
Claim Rejections - 35 USC § 103 (Modified)
10. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
11. Claims 1, 5, and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Roche Diagnostics GmbH (2020) (hereafter referred as Roche 2020) further in view of Mulchandani et al 2021 (Journal of Clinical Virology 136 (2021) 104739), Iankov et al 2021 (Journal of Immunological Methods 492 (2021) 112996), Zava et al 2020 (Bioanalysis. 2021 Jan;13(1):13-28), and Long et al 2020 (Nature Medicine, vol 26, June 2020, p. 845–848), Fontaine et al 2021 (Pract Lab Med. 2021 May;25: e00234), Bobbitt 2021 (PDF print out, online publication 2021), and DeVeaux et al 2018 (Stat Interface. 2018;11(4):699-707).
Claims 1, 5, 14-16: Roche 2020 is in the SARS CoV-2 antibody assay art and teaches a method for measuring and reporting an antibody against SARS CoV-2 in human plasma or serum sample (wet sample) using an electrochemiluminescence immunoassay “ECLIA” performed on cobas e immunoassay analyzers. The Elecsys Anti-SARS-CoV-2 assay uses a recombinant protein representing the nucleocapsid (N) antigen for the determination of antibodies against SARS-CoV-2. The test principle is a sandwich (antigen-test antibody-antigen) assay, and the required duration is approximately 18 minutes. The test is intended for use as an aid in adaptive immune response to SARS‑CoV‑2, indicating recent or prior infection (See, page 1, col 1).
The test involves different steps:
1st incubation: 20 μL of sample (cobas e 411, cobas e 601, and cobas e 602 analyzers) or 12 μL of sample (cobas e 801 analyzer), biotinylated SARS‑CoV‑2‑specific recombinant antigen and SARS‑CoV‑2‑specific recombinant antigen labeled with a ruthenium that form a sandwich complex if the antibody is specific to the SARS CoV-2 recombinant antigens;
2nd incubation: after addition of streptavidin-coated microparticles, the complex becomes bound to the solid phase via interaction of biotin and streptavidin;
the reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances and antibodies or immunoglobulins and proteins are then removed with ProCell/ProCell M/ProCell II M;
application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier
results are determined automatically by the software by comparing the electrochemiluminescence signal obtained from the reaction product of the sample with the signal of the cutoff value previously obtained by calibration (See, page 1, col 2). The result of a sample is given either as reactive or non-reactive as well as in the form of a cutoff index (COI; signal sample/cutoff). The negative control has a target value range of COI < 0.8 (qualitative assay result “non-reactive”). Results obtained with the Elecsys Anti‑SARS‑CoV‑2 assay can be interpreted as follows: COI <1.0 is considered as non-reactive that is interpreted as Negative for anti-SARS-CoV-2 antibodies. COI ≥ 1.0 is considered as reactive that is interpreted as Positive for anti-SARS-CoV-2 antibodies (See, page 4, col 1). The magnitude of the measured result above the cutoff is not indicative of the total amount of antibody present in the sample. The individual immune response following SARS‑CoV‑2 infection varies considerably and might give different results with assays from different manufacturers. Results of assays from different manufacturers should not be used interchangeably (See, Roche 2020, reference information 09203079501V2.0, Elecsys Anti‑SARS‑CoV‑2 cobas e 801). It is obvious that the claimed cutoff index (COI) indicative defining a sample positive COI >2.0 is rendered obvious by Roche 2020 of COI ≥ 1.0 (Roche 2020), the claimed negative sample COI <0.65 is rendered obvious by Roche 2020 of COI < 1.0 (Roche 2020). It is obvious that application of the assay for testing of antibodies eluted from DBS would result in dilution factor and the dilution factor would need to be considered to calculate COI and applied for obtaining the corresponding positive or negative COI.
Roche 2020 disclosed laboratories within the United States and its territories are required to report all positive results to the appropriate public health authorities (See, col 1 para 3).
Roche 2020 do not teach a dried sample or dried blood spot sample or dried plasma spot sample from a SARS CoV-2 infected or vaccinated human or a subject and extraction of analyte (antibody) from dried blood spot sample or dried plasma spot sample. Roche 2020 do not teach a COI for the assay categorized into a third category indeterminate or non-determinate.
Mulchandani et al 2021 is in the art and teaches use of dried blood spot samples for SARS-CoV-2 antibody detection using the Roche Elecsys ® high throughput immunoassay and compared antibody detection in DBS eluates with antibody detection in paired plasma samples, using the same assay as recited supra by Roche 2020, elution of antibody from DBS (See, abstract, page 2 col 1 section 2.3 DBS collection, col 2 section 2.4-2.5, Fig 2 DBS). The limit of detection for DBS is about 30 times higher than for plasma. DBS use for SARS-CoV-2 serology, though feasible, is insensitive relative to immunoassays on plasma, this means that the lowest concentration of an antibody detectable in a DBS sample may be significantly higher than in a plasma sample. DBS sample quality impacts on assay performance. Alternatives, including the collection of capillary blood samples, should be considered for screening programs (See, abstract). The assay interpretation is based on the manufacturer’s instruction on COI as recited supra in Roche 2020 (See, page 2, col 2 section 2.4). Mulchandani et al 2021 teaches testing of plasma samples as recited supra and DBS collection system (See, Fig 2 for DBS spots), therefore it would been obvious to prepare Dried plasma spot samples from SARS CoV-2 infected or vaccinated subject (instant claim 5 limitation).
Roche 2020 by using wet blood/plasma sample or Mulchandani et al 2021 by using dry spot blood/plasma sample do not teach COI for the assay categorized into a third category indeterminate or non-determinate.
Iankov et al 2021 teaches the limitation on dried blood spot sample (DBS) by disclosing immunoglobulin extraction from DBS, serum or other biological fluids loaded on filter paper cards could represent a valuable method of specimen preservation in monitoring immune response against pathogens as well as vaccination efficiency and demonstrates use of DBS or dried undiluted serum perverse antibody activity for immunoassay. The circles with known volume of human serum, mouse serum, purified MAbs and hybridoma culture supernatants MAbs were cut out from the filter cards (See, abstract, page 3, col 1 section 2.6).
Zava et al 2020 is in the SARS CoV-2 (COVID-19) art and teaches validation of dried blood spot (DBS) sample modifications to two commercially available COVID-19 IgG antibody immunoassays and teaches DBS IgG S1 assay and categorization of the test results into three categories, negative, indeterminate and positive, based on the absorbance cutoffs of <0.24, 0.24–0.3 and >0.3, respectively. In a second assay, the DBS IgG NCP assay the negative, indeterminate and positive cutoffs absorbance were <0.24, 0.24–0.26 and >0.26, respectively, used at the laboratory only (See, page 11, Fig 4, para 1, entire article). Zava et al 2020 further teaches that utilization of dried blood spots (DBS) as an alternative to serum, plasma or whole blood samples for laboratory analysis has been used for well over a half-century (See, page 1, para 2). Zava et al 2020 however do not teach calculation of cutoff index (COI).
The teachings of Roche 2020 and Mulchandani 2021 on COI values and Zava et al 2020 on absorbance values are “equivalent to be indicative of making an assay inference decision for a SARS CoV-2 infected or vaccinated subject DBS as positive, negative or not determinate” therefore renders obvious the claim 1 limitation (d) COI numerical values indicative of SARS CoV-2 infected or vaccinated subject DBS as positive, negative or not determinate.
Iankov et al 2021 further teaches the limitation, wherein the COI is calculated to incorporate dilution of the sample that occurs during extraction of the SARS-CoV-2 specific analyte from the dried sample by disclosing the dilution factor was calculated based on the volume loaded on the filter paper and extracted in the elution buffer volume. Iankov et al 2021 takes into account the dilution factor of DBS spot or dried serum spot by disclosing small 3 mm diameter size punches from the main DBS circle are sufficient for extraction and subsequent analysis (See, page 1, introduction col 2). The lower dilutions for detection of serological response to SARS-CoV-2 would require DBS extraction protocols that result in corresponding to recommended dilutions. Thus, parameters of immunoglobulin extraction from DBS, including the actual IgG concentration and antibody specific activity specific are necessary for optimization and development of an accurate SARS-CoVo2 laboratory diagnostic assay (See, page 2, col 1). We calculated that IgG extracted from 3 mm punches corresponded to 1.5 to 3.5 µl blood. The assay run in 96-well plates requires sample volume of 50–100 µl. Thus, extraction of the 3 mm disks in larger than 100 µl volume would result in a suboptimal dilution factor that subsequently requires modification of cut-off values increasing the risk of high false-positive or false-negative rates. (See, page 7, col 2). If the specimen is DBS, the best approach would be to excise an entire circle form the filter cards and elute it in 200–500 µl serum-free medium (See, page 8, col 1).
The same volume of frozen stored original supernatants was diluted in the extraction buffer to the corresponding dilutions and used as controls (See, page 3, col 2, section 3.1. Antibodies extracted from dried filter paper spots).
Long et al 2020 is in the art and teaches the limitation, wherein the measured value is divided by a fractional cutoff to account for the dilution so as to provide a normalized COI value by disclosing detection and quantification of IgG and IgM antibody responses to SARS-CoV-2 in patients with COVID-19 using magnetic chemiluminescence enzyme immunoassay (MCLIA). Antibody levels were presented as the measured chemiluminescence values divided by the cutoff (absorbance/cutoff, S/CO): S/CO (COI)> 1 was defined as positive and S/CO (COI) ≤1 as negative. (See, abstract, page 849, methods, col 1, definition and Detection of IgG and IgM against SARS CoV-2).
Fontaine et al 2021 is in the art and disclosed analysis of SARS-CoV-2 antibodies from dried blood spot samples with the Roche Elecsys Immunochemistry method. Results are reported based on numeric values in form of a cutoff index (COI) as well as in form of qualitative results non-reactive (COI < 1.0; negative) and reactive (COI ≥ 1.0; positive), (See, page 2, methods section 2.1. Analyzer system). A LOINC Code 95825-6 was generated to use this analytical approach with current Electronic Medical Record systems and to report results to public health authorities (See, page 6, conclusion).
Bobbitt 2021, and DeVeaux et al 2018 teaches a Bernoulli trial 10% condition for clinical trial sampling requirement for an experiment with only two possible outcomes – “success” or “failure” – and the probability of success is the same each time the experiment is conducted. As long as the sample size is less than or equal to 10% of the population size, one can make the assumption that Bernoulli trials are independent, and it is a routine requirement in the clinical trial art for serological diagnostic assay development and validations. Therefore, it would have been obvious to one of the ordinary skills in the art for statistical validity and analysis purposes to have the indeterminate range COI comprise less than 10% of the testing population.
The combined teachings of Roche 2020, Muclcandani et al 2021, Zava et al 2020, Long et al 2020 renders obvious the instant claims 1, 5, 14-16 by teachings the COI values “equivalent” to make a decision or conclude the DBS based SARS CoV-2 antibody assay COI results as positive, negative, indeterminate although does not exactly teach the cutoff index (COI) values as claimed in claim limitation (d) cutoff index (COI) indicative defining a sample positive (COI >2.0), negative sample (COI <0.65) or not determinate sample (COI >0.65 to <2.0).
According to MPEP § 2144.05, generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.") See MPEP § 2144.05.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). A range can be disclosed in multiple prior art references instead of in a single prior art reference depending on the specific facts of the case. Iron Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1322, 73 USPQ2d 1225, 1228 (Fed. Cir. 2004).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior art teachings of Roche 2020 on serum or plasma (wet sample) to incorporate the prior art teachings of Mulchandani et al 2021 on DBS and plasma, and dried serum spot of Iankov et al 2021, Zava et al 2020, and Long et al 2020 categorization of the assay results into positive, negative and indeterminate based on the SARS CoV-2 antibody diagnostic assay COI and Bobbitt 2021, and DeVeaux et al 2018 on less than 10% testing population for the indeterminate range COI to arrive at the invention of claim 1, 5 and 14-16. The motivation to use DBS or dried plasma spot sample would be simplify a protocol for collection, transport and storage of the sample (See, Iankov et al 2021), the motivation for use of dried plasma spot sample would be to increase sensitivity of the assay and avoid variability of DBS performance due to hematocirit and immunoglobulin concentration in context to DBS spot volume verse dried plasma spot volume (See, abstract of Mulchandani et al 2021, and Iankov et al 2021 page 8 col 1) for measuring the antibody in subjects and report the diagnostic results for commercial success. One of ordinary skill in the art would have a reasonable expectation of success to arrive at the invention of claims 1, 5 and 14-16 given the combined prior art teachings applied to render obvious the invention of claims 1, 5 and 14-16 as recited supra. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A-B and E-G.
12. Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Roche Diagnostics GmbH (2020) (hereafter referred as Roche 2020) further in view of Mulchandani et al 2021 (Journal of Clinical Virology 136 (2021) 104739), and Zava et al 2020 (Bioanalysis. 2021 Jan;13(1):13-28), Iankov et al 2021 (Journal of Immunological Methods 492 (2021) 112996), Long et al 2020 (Nature Medicine, vol 26, June 2020, p. 845–848), and Fontaine et al 2021 (Pract Lab Med. 2021 May;25: e00234), Bobbitt 2021 (PDF print out, online publication 2021), and DeVeaux et al 2018 (Stat Interface. 2018;11(4):699-707), as applied to claims 1, 5 and 14-16 above, and additional teachings of Mulchandani et al 2021 (Journal of Clinical Virology 136 (2021) 104739), and Long et al 2020 (Nature Medicine, vol 26, June 2020, p. 845–848).
The combined teachings of Roche 2020, Mulchandani et al 2021, Zava et al 2020 and Iankov et al 2021, Long et al 2020, Fontaine et al 2021, Bobbitt 2021, and DeVeaux et al 2018 that rendered obvious claims 1, 5 and 14-16 as recited supra are incorporated here in entirety. The added limitation of instant claim 9 on COI for serum sample is taught by the prior art teachings of Mulchandani et al 2021 and Long et al 2020 as recited below.
Mulchandani et al 2021 teaches the study aimed to compare antibody detection in DBS eluates using the Roche Elecsys® immunoassay with antibody detection in paired plasma samples, using the same assay and thus renders obvious claim 9 limitation wherein the normalized COI comprises a cutoff value for serum (See, abstract).
Long et al 2020 further teaches limitation, wherein the normalized COI comprises a cutoff value for serum by disclosing a total of 363 serum samples from patients, MCLIA assay to detect and quantify SARS CoV-2 IgG and IgM antibodies in serum samples, the antibody titer was tested once per serum sample and calculation of the COI and thus comprises a cutoff value for serum COI antibody levels were presented as the (COI)> 1 was defined as positive and S/CO (COI) ≤1 as negative (See, abstract, page 849, methods col 1, study design, definition and detection of IgG and IgM against SARS CoV-2).
According to MPEP § 2144.05, generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.") See MPEP § 2144.05.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). A range can be disclosed in multiple prior art references instead of in a single prior art reference depending on the specific facts of the case. Iron Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1322, 73 USPQ2d 1225, 1228 (Fed. Cir. 2004).
It would have been obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to modify the combined prior art teachings as applied to claims 1 above with the additional teachings of Iankov et al 2021 on DBS or dried serum spot dilution factor, and Mulchandani et al 2021 on use of paired plasma samples use for dilution factor and Long et al 2020 on COI mathematical calculation including cutoff value for serum to arrive at the invention of claim 9. The motivation for using mathematical calculation involving the measured value is divided by a fractional cutoff to account for the dilution so as to provide a normalized COI value would be to account for dilution factor introduced by a small area size DBS punctured from the whole DBS and used for elution of the sample (See, Iankov et al 2021). The combined teachings of Mulchandani et al 2021, and Iankov et al 2021 would result in arrival at a SARS CoV-2 antibody based diagnostic assay that uses a normalized Cut-Off Index (COI) based on accounting for DBS sample elution and dilution introduced fractional cutoff and would offer advantages for inference of the results in improving the precision and reliability of results, distinguishing between positive and negative samples and non-determinate samples, standardize results across different laboratories leading to more consistent interpretations and reporting. Normalization and cutoff index calculation by dividing the measured value by this fractional cutoff (DBS sample elution dilution factor), a normalized cutoff index is generated. This index accounts for the dilution and allows for a more standardized comparison of results across different dilutions and different assay formats or laboratories. A normalized COI for SARS CoV-2 antibody assay would also allow for the establishment of specific thresholds for reactivity, enhancing sensitivity and specificity of the assay among infected or vaccinated subjects (See, Roche 2020, Mulchandani 2021 and Zava et al 2020) and for commercial success. The motivation would also have a commercial interest to market the assay as a kit with a normalized COI (See, Iankov et al 2021, Mulchandani 2021, Long et al 2020). One of ordinary skill in the art would have a reasonable expectation of success to arrive at the invention of claim 9 given the combined prior art teachings applied to render obvious the invention of claim 9 as recited supra. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A-B and E-G.
Response to Applicant’s Arguments
13. Applicant’s arguments with respect to claim(s) 11/21/2025 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
(i). Applicant’s argument 1: Claim Rejections Under 35 U.S.C. Section 103 :
Claims 1, 5 and 13-16 are rejected under 35 U.S.C. § 103 as being unpatentable over Roche Diagnostics GmbH (2020) (" Roche 2020") further in view Mulchandani et al 2021 (Journal of Clinical Virology 136 (2021) 104739) ("Mulchandani"), Iankov et al 2021 (Journal of Immunological Methods 492 (2021) 112996) ("Iankov"), and Zava et al 2020 (Bioanalysis, 2021 Jan;13(1):13-28) ("Zava"). Claim 13 is cancelled herein, rendering its rejection moot. Applicant respectfully traverses the rejection.
Independent claim 1 has been amended to recite:
A method for reporting a dried blood spot sample as being positive, negative, or indeterminate for SARS-CoV-2 comprising:
(a) obtaining a dried sample from a subject, wherein the dried
sample is a dried blood spot;
(b) extracting an antibody to SARS-Co-V-2 from the sample;
(c) measuring the antibody using a sandwich assay employing a
first antigen labeled with a detectable moiety and a second antigen labeled
with a binding agent; and
(d) providing a cutoff index (COI) indicative of whether the
subject has a detectable amount of the antibody and so is defined as positive, does not have a detectable amount of the antibody and so is defined as negative, or has an amount of antibody that is not determinate as being either positive or negative for the antibody, wherein the COI
for a positive sample is greater than 2.0, the COI for a negative sample is less than 0.65 and the COI for an indeterminate sample is > 0.65 COI and < 2.0 COI,
wherein the indeterminate range is asymmetric with 1.0 representing the
negative/positive cutoff, wherein the indeterminate range comprises less than 10% of the testing population, wherein the COI is calculated to incorporate dilution of the sample that occurs during extraction of the antibody to SARS-CoV-2 from the dried
sample, and wherein the measured value is divided by a fractional cutoff to account for
the dilution so as to provide a normalized COI value.
To establish a prima facie case of obviousness, the Office must establish that the cited art discloses or suggests all elements of the claimed invention, that there was a motivation to combine the references, and that there was a reasonable expectation of success in doing so. "[R]ejections on obviousness cannot be sustained by mere conclusory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness." KSR International Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007) (quoting In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006)).
Applicant respectfully submits that the cited art at least fails to disclose or suggest all
elements of amended independent claim 1. None of the cited art teaches reporting a dried blood spot sample as being positive, negative, or indeterminate for SARS-CoV-2, wherein the 0 COI, wherein the indeterminate range is asymmetric with 1.0 representing the negative/positive cutoff, and wherein the indeterminate range comprises less than 10% of the testing population. The claimed cutoffs for negative and positive samples have the advantage of being outside of the range for false positive results when using the methods disclosed herein, unlike the COIs disclosed in the cited art. See para. [0082] of the application as published. Furthermore, the use of an asymmetric indeterminant region around the cutoff maximizes the negative and positive predictive values of the methods claimed COI for a positive sample is greater than 2.0, the COI for a negative sample is less than 0.65 and the COIfor an indeterminate sample is > 0.65 COI and 2. herein relative to the assays disclosed in the prior art. See, e.g., paras. [0036] and [0067] of the application as published. As the cited art fails to disclose or suggest all the elements of amended independent claim 1, one of skill in the art would not and could not arrive at the highly predictive methods claimed herein from the disclosures of the cited art.
For at least this reason, Applicant submits that amended independent claim 1 and its
dependent claims 5 and 14-16 are not obvious over Roche 2020, Mulchandani, Zava, and Iankov, alone or in combination. Thus, Applicant requests the rejection of claims 1, 5, and 14-16 under 35 U.S.C. § 103 be withdrawn.
Claims 7-9 are rejected under 35 U.S.C. § 103 as being unpatentable over combined
teachings of Roche 2020 further in view of Mulchandani, Zava, and Iankov as applied to claims 1, 5 and 13-16 and further in view of Long et al. 2020 (Nature Medicine, vol 26, June 2020, p. 845-848) ("Long"). Claims 7 and 8 have been cancelled herein, as the limitations of these claims have been incorporated into claim 1, thereby rendering their rejection moot. Further, Applicant respectfully submits that for the reasons above and below, Roche 2020, in view of Mulchandani, Iankov, Zava, and Long does not render amended claim 1 obvious. Applicant respectfully traverses the rejection of claim 9.
Claim 9 depends from amended claim 1, which Applicant submits is not obvious for the reasons set forth above. Long fails to cure the deficiencies of Roche 2000, Mulchandani, Zava, and Iankov. Thus, Applicant respectfully submits that claim 9 is not obvious over Roche 2000, Mulchandani, Zava, Iankov, and Long, alone or in combination, and requests the rejection of claim 9 under 35 USC § 103 be withdrawn.
In Response: Applicant’s arguments have been considered and are not persuasive in view of the modified rejection under 35 U.S.C. 103 in response to the amended claim 1 that affected dependent claims. In response to the amendment additional teachings from the previously cited prior arts have been applied and additional prior arts were introduced as recited in the rejection.
The rejection of the amended claims 1, 5, 9 and 14-19 under 35 U.S.C. 103 is maintained.
Double Patenting
14. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
15. Claims 1, 5, 9, and 14-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of copending Application No. 18/205,255 in view of combined prior art teachings of Roche Diagnostics GmbH (2020) (hereafter referred as Roche 2020), Mulchandani et al 2021 (Journal of Clinical Virology 136 (2021) 104739), Zava et al 2020 (Bioanalysis. 2021 Jan;13(1):13-28), Iankov et al 2021 (Journal of Immunological Methods 492 (2021) 112996), Long et al 2020 (Nature Medicine, vol 26, June 2020, p. 845–848), Bobbitt 2021 (PDF print out, online publication 2021), and DeVeaux et al 2018 (Stat Interface. 2018;11(4):699-707), as applied to claims 1, 5, 7-9 and 13-16, as recited supra.
Both the instant claims 1, 5, 9, and 14-16 and co-pending application no. 18/205,255 claims 1-11 are directed to detection of SARS CoV-2 antibodies in DBS, dried plasma spot samples using SARS CoV-2 antibody detection assays e.g. ELISA or ECLIA assay.
The difference is that copending application claims 7-11 are directed to recognition of SARS CoV-2 infected or vaccinated subject antibodies to SARS CoV-2 spike protein. The instant claims 1, 5, 9, and 14-16 do not specify the antigen and therefore could include any SARS CoV-2 antigen e.g S protein or fragment of S protein; N protein or fragment of N protein. The instant claims have limitations on COI for inference of the assay whereas the copending reference claims 1-11 has claim limitation as semi-quantitative or quantitative inference of the assay.
The prior art teachings as as applied for obviousness rejection under 35 U.S.C. 103 for claims 1, 5, 9, and 14-16 as recited supra are incorporated by reference here in entirety including teachings, motivations, and reasonable expectation of success to render obvious to modify the copending claims 1-11 to arrive at the instant claims 1, 5, 9, and 14-16.
Instant claims 1, 5, 9, and 14-16 are rendered obvious by copending claims 1-11 in view of the prior arts as incorporated by reference as recited supra for the provisionally rejected on the ground of nonstatutory double patenting.
This is a provisional nonstatutory double patenting rejection.
Response to Applicant’s Arguments (filed on 11/21/2025)
(ii) Applicant’s argument: Double Patenting Rejection
Claims 1, 5, 7-9 and 13-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of copending Application No. 18/205,255 in view of combined prior art teachings of Roche Diagnostics GmbH (2020) (hereafter referred as Roche 2020), Mulchandani et al. 2021 (Journal of Clinical Virology 136 (2021) 112996), and Long et al 2020 (Nature Medicine, vol 26, June 2020, p. 845-848) as applied to claims 1, 5, 7-9 and 13-16, as recited supra. Claims 7-8 and 13 have been cancelled, rendering their rejection moot.
Applicant respectfully submits that, as the cited art fails to teach each and every
limitation of amended independent claim 1, the cited art cannot render the methods claimed herein obvious over claims 1-11 of copending Application No. 18/205,255 in view of combined prior art teachings. Thus, Applicant requests the provisional nonstatutory double patenting rejection of claims 1, 5, 9, and 14-16 be withdrawn.
In Response: Applicant’s arguments against the double patenting rejection have been considered and are not persuasive in view of the modified rejection under 35 U.S.C. 103, as recited supra, in response to the amended claim 1 that affected dependent claims. In response to the amendment additional teachings from the previously cited prior arts have been applied and additional prior arts were introduced as recited in the rejection.
The provisional nonstatutory double patenting rejection of the amended claims 1, 5, 9 and 14-19 is maintained.
16. Relevant Prior Arts.
Roche Diagnostics International Ltd (2020). Elecsys® Anti-SARS-CoV-2 S Immunoassay for the quantitative determination of antibodies to the SARS-CoV-2 spike protein. The publication teaches the assays with SARS CoV-2 Spike antigen for measurement and detection of anti-SARS CoV-2 antibodies in a sample.
Amendola et al 2021. Dried Blood Spot as an Alternative to Plasma/Serum for SARS-CoV-2 IgG Detection, an Opportunity to Be Sized to Facilitate COVID-19 Surveillance Among Schoolchildren. Pediatr Infect Dis J. 2021 Jan;40(1):e46-e47.
Whitman et al 2020. Evaluation of SARS-CoV-2 serology assays reveals a range of test performance. Nat Biotechnol. 2020 Oct;38(10):1174-1183.
Liu, T., Hsiung, J., Zhao, S. et al. Quantification of antibody avidities and accurate detection of SARS-CoV-2 antibodies in serum and saliva on plasmonic substrates. Nat Biomed Eng 4, 1188–1196 (2020).
Lau CS, Hoo SP, Yew SF, Ong SK, Lum LT, Heng PY, Tan JG, Wong MS, Aw TC. Evaluation of an Electrochemiluminescent SARS-CoV-2 Antibody Assay. J Appl Lab Med. 2020 Nov 1;5(6):1313-1323.
Omata et al 2021. The dynamic change of antibody index against Covid-19 is a powerful diagnostic tool for the early phase of the infection and salvage PCR assay errors. J Microbiol Immunol Infect. 2021 Oct;54(5):830-838.
Duggan et al 2021. Evaluation of Roche Elecsys Anti-SARS-CoV-2 S serology assay for the detection of anti-SARS-CoV-2 S antibodies.
Public Health England. May 2021. (Evaluation of Roche Elecsys AntiSARS-CoV-2 S serology assay for the detection of anti-SARS-CoV-2 S antibodies. (May 2021).
Conclusion
17. No claim is allowed.
18. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
19. A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Primary Examiner, Art Unit 1600